Refining method

ABSTRACT

A refining method according to the present invention is a refining method for crystallizing a compound with at least one crystal form, including setting, as a target wavelength and a target concentration, a specific infrared wavelength and a specific concentration at which a specific crystal form precipitates from a solution of the compound dissolved in a solvent, and using an infrared radiation apparatus capable of emitting infrared radiation including the target wavelength to evaporate the solvent and precipitate the specific crystal form while irradiating a solution of the compound dissolved in the solvent at the target concentration with infrared radiation including the target wavelength.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a refining method.

2. Description of the Related Art

Distillation, recrystallization, chromatography, extraction, and thelike are generally known as methods for refining a target organiccompound. Patent Literature 1 discloses a method for refining an organiccompound using a laser beam. In Patent Literature 1, to selectivelyproduce a metastable substance from a solution of a substance containinga stable form and a metastable form as crystal forms, metastablecrystals are selectively produced by emitting a laser beam into thesolution to generate bubbles and form metastable crystal nuclei.

CITATION LIST Patent Literature

PTL 1: Japanese Unexamined Patent Application Publication No.2014-189462

SUMMARY OF THE INVENTION

In Patent Literature 1, however, the laser beam is emitted to generatebubbles in the solution, and no attention is paid to light of aninfrared absorption wavelength.

The present invention has been made to address such an issue and mainlyaims to obtain a specific crystal form from a solution of a compounddissolved in a solvent.

A refining method according to the present invention is a refiningmethod for crystallizing a compound with at least one crystal form,including: setting, as a target wavelength and a target concentration, aspecific infrared wavelength and a specific concentration at which aspecific crystal form precipitates from a solution of the compounddissolved in a solvent, and using an infrared radiation apparatuscapable of emitting infrared radiation including the target wavelengthto evaporate the solvent and precipitate the specific crystal form whileirradiating a solution of the compound dissolved in the solvent at thetarget concentration with infrared radiation including the targetwavelength.

This refining method can precipitate a specific crystal form from asolution of a compound dissolved in a solvent by adjusting the solventfor dissolving the compound, the infrared radiation emitted to thesolution, and the concentration of the compound in the solution. Thereason why a specific crystal form precipitates is not clear but isconsidered as described below. A compound with a plurality of crystalforms generally has a dissolution rate depending on the type of solvent.The dissolution rate is probably related to the ease of precipitation ofcrystals. Furthermore, a crystal form with higher infrared absorptivityprobably has more active thermal vibrations and fewer crystal nuclei.Furthermore, the crystal form precipitated from the solution alsodepends on the concentration of the compound in the solution. It istherefore thought that the suitable conditions for precipitation of aspecific crystal form depend on the solvent for dissolving the compound,the infrared radiation emitted to the solution, and the concentration ofthe compound in the solution.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a refining apparatus 1 (partially incross section).

FIG. 2 is a partial bottom view of an infrared heater 10.

FIG. 3 is a graph of an infrared absorption spectrum of febuxostat.

FIG. 4 is a graph of an infrared absorption spectrum of loxoprofen.

FIG. 5 is a graph of an infrared absorption spectrum of carbamazepine.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of the invention are described in detail below.

A refining method according to the present embodiment is a refiningmethod for crystallizing a compound with at least one crystal form,including: setting, as a target wavelength and a target concentration, aspecific infrared wavelength and a specific concentration at which aspecific crystal form precipitates from a solution of the compounddissolved in a solvent, and using an infrared radiation apparatuscapable of emitting infrared radiation including the target wavelengthto evaporate the solvent and precipitate the specific crystal form whileirradiating a solution of the compound dissolved in the solvent at thetarget concentration with infrared radiation including the targetwavelength.

The compound may have a plurality of crystal forms or a single crystalform.

In one example described below, a specific crystal form is precipitatedby evaporating a solvent from a solution of a raw material of an organiccompound X with two crystal forms a1 and a2 dissolved in the solvent.The specific crystal form is precipitated on the basis of the results ofpreliminary experiments. In a first preliminary experiment, it isassumed that a crystal form a1 is precipitated when a solution of theraw material of the organic compound X dissolved in a solvent p1 at aspecific concentration C1 [mg/mL] is irradiated with infrared radiationincluding a wavelength λ1 [µm] (for example, infrared radiation having apeak at the wavelength λ1) to evaporate the solvent p1. In a secondpreliminary experiment, it is assumed that a crystal form a2 isprecipitated when a solution of the raw material of the organic compoundX dissolved in the solvent p1 at a specific concentration C2 [mg/mL] isirradiated with infrared radiation including the wavelength λ1 [µm] toevaporate the solvent p1. In such a preliminary experiment, toprecipitate the crystal form a1, the solvent p1 used in the firstpreliminary experiment, infrared radiation including the wavelength λ1[µm] , and the concentration C1 of the compound in the solution [mg/mL]are employed. To precipitate the crystal form a2, the solvent p1 used inthe second preliminary experiment, infrared radiation including thewavelength λ1 [µm] , and the concentration C2 of the compound in thesolution [mg/mL] are employed. Although different crystal forms areprepared by changing the concentration of the compound in the solutionwith the same solvent at the same wavelength in this embodiment, thepresent invention is not limited to the embodiment. Different crystalforms may be prepared by appropriately changing the combination ofsolvent, wavelength, and compound concentration. For example, differentcrystal forms may be prepared by changing the solvent at the samewavelength and at the same compound concentration. Alternatively,different crystal forms may be prepared by changing the wavelength withthe same solvent at the same compound concentration.

The wavelength λ1 [µm] is preferably determined on the basis of aninfrared absorption spectrum of a crystal form and the dissolution rateof a raw material in a solvent. Crystal forms often have differentinfrared absorption spectra and often have different absorptivities at agiven wavelength. It is thought that when a solution is irradiated withinfrared radiation including a certain wavelength, a crystal form with ahigher absorptivity at the wavelength has more active thermal vibrationthan crystal forms with a lower absorptivity, has fewer crystal nuclei,and is less likely to precipitate. On the other hand, it is thought thata crystal form that can easily form crystal nuclei is different betweena solvent with a high dissolution rate of a raw material and a solventwith a low dissolution rate of a raw material. Thus, the wavelength λ1[µm] is preferably determined on the basis of an infrared absorptionspectrum of a crystal form and the dissolution rate of a raw material ina solvent. For example, the infrared radiation including the wavelengthλ1 [µm] may be infrared radiation having a peak at the wavelength λ1[µm] .

In the following example, a crystal form c is precipitated byevaporating a solvent q from a solution of an organic compound Y withthe crystal form c dissolved in the solvent q. It is assumed that, in apreliminary experiment, the crystal form c precipitates when the solventq is evaporated while the solution of the organic compound Y dissolvedin the solvent q at a concentration c1 [mg/mL] is irradiated withinfrared radiation including a wavelength α [µm]. It is also assumedthat the crystal form c does not precipitate and is amorphous when thesolvent q is evaporated while the solution of the organic compound Ydissolved in the solvent q at a concentration c2 [mg/mL] is irradiatedwith infrared radiation including the wavelength α [µm]. In such a case,to precipitate the crystal form c, the solvent q may be evaporated whilethe solution of the organic compound Y dissolved in the solvent q at aconcentration c1 [mg/mL] is irradiated with infrared radiation includingthe wavelength α [µm]. For example, the infrared radiation including thewavelength α [µm] may be infrared radiation having a peak at thewavelength α [µm] .

Examples of compounds that can be refined by the refining methodaccording to the present embodiment include, but are not limited to,febuxostat, terfenadine, indomethacin, ibuprofen, loxoprofen, caffeine,diclofenac, and carbamazepine. Examples of the solvent for dissolving araw material of a compound include, but are not limited to, alcoholsolvents, such as methanol, ethanol, 1-propanol, 2-propanol (isopropanol(IPA)), 1-butanol, 2-butanol, isobutanol, and tert-butanol; nitrilesolvents, such as acetonitrile and propionitrile; ether solvents, suchas diethyl ether and tetrahydrofuran; ketone solvents, such as acetoneand methyl ethyl ketone; halogen solvents, such as dichloromethane andchloroform; ester solvents, such as ethyl acetate and methyl acetate;aliphatic hydrocarbon solvents, such as pentane, hexane, heptane,octane, and cyclohexane; aromatic hydrocarbon solvents, such as benzene,toluene, and xylene; and mixed solvents of alcohol solvents and water.

In the refining method according to the present embodiment, any infraredradiation apparatus capable of emitting infrared radiation including awavelength λ [µm] can be used. For example, the infrared radiationapparatus may include a sheet radiator and a planar heater serving as aheat source. The infrared radiation apparatus is preferably an infraredradiation apparatus capable of emitting infrared radiation having a peakat the wavelength λ [µm], particularly infrared radiation having a peakat the wavelength λ [µm] and having a narrow half-width. Examples ofsuch an infrared radiation apparatus include metamaterial emitters andinfrared radiation apparatuses with a filter. Examples of themetamaterial emitters include emitters of a Metal-Insulator-Metal (MIM)type, a microcavity type, a meta-atom type, and a multilayer type.Examples of the MIM type include those described in Reference 1 (JSMETED Newsletter, No. 74, pp. 7-10, 2014). The MIM type is described indetail later. Examples of the microcavity type and the meta-atom typeinclude those described in Reference 2 (JSME TED Newsletter, No. 74, pp.2-6, 2014). Examples of the multilayer type include those described inReference 3 (ACS Cent. Sci., Vol. 5, pp. 319-326, 2019). Examples of theinfrared radiation apparatuses with a filter include infrared heatersdescribed in Japanese Patent No. 6442355.

FIG. 1 is a perspective view of a refining apparatus 1 partially incross section. FIG. 2 is a partial bottom view of an infrared heater 10.The horizontal direction, the front-back direction, and the verticaldirection are as illustrated in FIG. 1 .

The refining apparatus 1 is an apparatus for precipitating a specificcrystal form from a solution 22 in a flat laboratory dish 20 using theinfrared heater 10. The solution 22 contains a compound with a pluralityof crystal forms dissolved in a solvent.

The infrared heater 10 is an example of a metamaterial emitter of theMIM type and includes a heater body 11, a structure 30, and a casing 70.The infrared heater 10 emits infrared radiation to the solution 22 inthe flat laboratory dish 20 located under the infrared heater 10.

The heater body 11 is configured as a planar heater and includes aheating element 12 in which a linear member is bent in a zigzag, and aprotective member 13, which is an insulator in contact with andsurrounding the heating element 12. The material of the heating element12 is, for example, W, Mo, Ta, an Fe—Cr—Al alloy, or a Ni—Cr alloy. Thematerial of the protective member 13 is, for example, an insulatingresin, such as a polyimide, or a ceramic. The heater body 11 is locatedinside the casing 70. Both ends of the heating element 12 are coupled toa pair of input terminals (not shown) attached to the casing 70.Electric power can be supplied to the heating element 12 from theoutside through the pair of input terminals. The heater body 11 may be aplanar heater with a ribbon-like heating element wound around aninsulator.

The structure 30 is a sheet radiator provided under the heating element12. The structure 30 includes a first conductor layer 31 (a metalpattern), a dielectric layer 34, a second conductor layer 35 (a metalsubstrate), and a supporting substrate 37 stacked in this order from theoutside to the inside under the infrared heater 10. The structure 30 islocated so as to close an opening in the lower portion of the casing 70.

As illustrated in FIG. 2 , the first conductor layer 31 is configured asa metal pattern with a periodic structure in which metal electrodes 32of the same shape and size are arranged at regular intervals on thedielectric layer 34. More specifically, the first conductor layer 31 isconfigured as a metal pattern in which a plurality of tetragonal metalelectrodes 32 are arranged at regular intervals D1 in the horizontaldirection and at regular intervals D2 in the front-back direction on thedielectric layer 34. The metal electrodes 32 have a shape with athickness (a vertical height) smaller than a lateral width W1 (a widthin the horizontal direction) and a longitudinal width W2 (a width in thefront-back direction). The metal pattern has a transverse period Λ1 =D1 + W1 and a longitudinal period Λ2 = D2 + W2. It is assumed that D1and D2 are the same, and W1 and W2 are the same. The material of themetal electrodes 32 is, for example, gold or aluminum (Al). The metalelectrodes 32 are bonded to the dielectric layer 34 via an adhesivelayer (not shown). The material of the adhesive layer is, for example,chromium (Cr), titanium (Ti), or ruthenium (Ru).

The dielectric layer 34 is a flat member with an upper surface bonded tothe second conductor layer 35. The dielectric layer 34 is locatedbetween the first conductor layer 31 and the second conductor layer 35.A portion of the lower surface of the dielectric layer 34 on which themetal electrodes 32 are not located is a radiation surface 38 foremitting infrared radiation to an object. The material of the dielectriclayer 34 is, for example, alumina (Al₂O₃) or silica (SiO₂) .

The second conductor layer 35 is a metal sheet with an upper surfacebonded to the supporting substrate 37 via an adhesive layer (not shown).The material of the second conductor layer 35 may be the same as thematerial of the first conductor layer 31. The material of the adhesivelayer is, for example, chromium (Cr), titanium (Ti), or ruthenium (Ru).

The supporting substrate 37 is a flat member fixed inside the casing 70with a fixing component or the like (not shown) and supports the firstconductor layer 31, the dielectric layer 34, and the second conductorlayer 35. The material of the supporting substrate 37 is, for example, amaterial, such as a Si wafer or glass, that can easily maintain a smoothsurface, has high heat resistance, and has low thermal warping. Thesupporting substrate 37 may be in contact with the lower surface of theheater body 11 or may be separated from the lower surface with a spacetherebetween. When the supporting substrate 37 is in contact with theheater body 11, they may be bonded together.

The structure 30 functions as a metamaterial emitter with thecharacteristics of selectively emitting infrared radiation of a specificwavelength. The characteristics probably result from a resonancephenomenon explained by magnetic polariton. The magnetic polariton is aresonance phenomenon in which a confinement effect of a strongelectromagnetic field can be produced in a dielectric (the dielectriclayer 34) between two upper and lower conductors (the first conductorlayer 31 and the second conductor layer 35). Thus, in the structure 30,a portion of the dielectric layer 34 between the second conductor layer35 and the metal electrodes 32 serves as an infrared radiation source.Infrared radiation emitted from the radiation source goes around themetal electrodes 32 and is emitted to the surrounding environment from aportion of the dielectric layer 34 on which the metal electrodes 32 arenot located (that is, from the radiation surface 38). In the structure30, the materials of the first conductor layer 31, the dielectric layer34, and the second conductor layer 35 and the shape and periodicstructure of the first conductor layer 31 can be adjusted to regulatethe resonance wavelength. Thus, infrared radiation emitted from theradiation surface 38 of the structure 30 characteristically has highemissivity at a specific wavelength. In the present embodiment, thematerial, shape, periodic structure, and the like are adjusted so thatthe structure 30 characteristically emits from the radiation surface 38infrared radiation having a maximum peak with a half-width of 2.0 µm orless (preferably 1.5 µm or less, more preferably 1.0 µm or less) andwith an emissivity of 0.7 or more (preferably 0.8 or more) in thewavelength range of 0.9 to 25 µm (preferably 2.5 to 25 µm (4000 to 400cm⁻¹) ). Thus, the structure 30 characteristically emits infraredradiation having a sharp maximum peak with a relatively small half-widthand a relatively high emissivity. The half-width is, for example, butnot limited to, preferably 2.0 µm or less, more preferably 1.5 µm orless, still more preferably 1.0 µm or less.

The casing 70 has an approximately rectangular parallelepiped shape witha space therein and with an open bottom surface. The heater body 11 andthe structure 30 are located in the space inside the casing 70. Thecasing 70 is formed of a metal (for example, stainless steel oraluminum) to reflect infrared radiation emitted from the heating element12.

An example of use of the refining apparatus 1 is described below. In thefollowing example, as a specific crystal form precipitated from asolution of the organic compound X with two crystal forms a1 and a2dissolved in a solvent, as described above, the crystal form a1 isprecipitated.

First, the flat laboratory dish 20 containing the solution 22 is placedunder the first conductor layer 31 of the infrared heater 10. Thesolution 22 contains the organic compound X dissolved in the solvent p1at the concentration C1 [mg/mL]. Next, electric power is supplied from apower supply (not shown) through an input terminal to both ends of theheating element 12. The electric power is supplied so that thetemperature of the heating element 12 reaches a preset temperature (forexample, but not limited to, several hundred degrees Celsius). Theheating element 12 heated to the predetermined temperature transfersenergy to the surroundings by at least one of three heat transfer modesof conduction, convection, and radiation and heats the structure 30.Consequently, the structure 30 is heated to a predetermined temperature,becomes a secondary radiator, and emits infrared radiation.

In this case, a predetermined wavelength λ1 [µm] is set as a targetwavelength, and infrared radiation having a peak at the wavelength λ1[µm] is set to be emitted from the structure 30. More specifically, theintervals D1 and D2 of the metal electrodes 32 of the structure 30, thewidths W1 and W2 of the metal electrodes 32, and the periods Λ1 and Λ2of the metal pattern are set so that infrared radiation emitted from thestructure 30 has a peak at a predetermined wavelength λ1 [µm] .Irradiation of the solution 22 in the flat laboratory dish 20 withinfrared radiation having a peak at the wavelength λ1 [µm] evaporatesthe solvent p1 of the solution 22 with the passage of time and finallyselectively precipitates crystals of the organic compound X with thecrystal form a1.

Although the infrared heater 10 is designed to mainly emit infraredradiation of a target wavelength, it is difficult to remove allradiation other than the target wavelength from the infrared radiationof the structure 30, and convective heat dissipation from components ofthe heater to the surroundings will occur in the atmosphere. To form anactual process, therefore, various considerations should be given to theshape of the apparatus and the like so that such associated heat flowdoes not excessively increase the temperature of raw materials and thelike.

The refining method according to the present embodiment described indetail above can precipitate a specific crystal form from a solution ofa compound dissolved in a solvent by adjusting the solvent fordissolving the compound, infrared radiation emitted to the solution, andthe concentration of the compound in the solution. Furthermore, the useof the infrared heater 10 of the MIM type allows a peak wavelength ofemitted infrared radiation to be designed to accurately match a targetwavelength. The first conductor layer 31 of the infrared heater 10 isconfigured as a metal pattern with a periodic structure in which themetal electrodes 32 of the same shape and size are arranged at regularintervals. The infrared heater 10 emits infrared radiation having a peakwavelength that changes with the lateral width W1 and the longitudinalwidth W2 of the metal electrodes 32. The lateral width W1 and thelongitudinal width W2 of the metal electrodes 32 can be accurate asdesigned, for example, by drawing and lift-off using a well-knownelectron-beam lithography system. Thus, a peak wavelength of infraredradiation emitted from the infrared heater 10 can be relatively easilyand accurately adjusted to a target wavelength.

It goes without saying that the present invention should not be limitedto these embodiments and can be implemented in various aspects withinthe technical scope of the present invention.

The metal electrodes 32 are tetragonal in these embodiments but may becircular. In circular metal electrodes 32, the diameter corresponds tothe lateral width W1 and the longitudinal width W2.

EXAMPLES Example 1

Febuxostat is known to have a plurality of crystal forms F1, F2, Q, andH1. FIG. 3 is a graph of an infrared absorption spectrum of each crystalform. Table 1 shows the absorptivity of each crystal form at wavelengthsof 3.7 and 6.7 µm in the infrared absorption spectra.

TABLE 1 Compound Crystal form Absorptivity (-) 3.0 ( µm) 3.7( µm) 6.7 (µm) Febuxostat F1 - 0.27 0.65 F2 - 0.21 0.56 Q - 0.05 0.40 H1 - 0.030.53 Loxoprofen F1 - 0.06 0.40 F2 - 0.10 0.55 Carbamazepine F1 0.44 -0.52 F2 0.50 - 0.60 F3 0.40 - 0.47 F4 0.47 - 0.55

A test sample was prepared by weighing 25 mg of febuxostat (product codeF0847, Tokyo Chemical Industry Co., Ltd.) into a flat laboratory dish(ϕ32 mm × 16 mm), adding 1 mL of isopropanol (IPA), heating thefebuxostat on a hot plate at 80° C. for 2 minutes, and dissolving thefebuxostat with slight stirring (the concentration of febuxostat in thetest sample was 25 [mg/mL] ) . The test sample was irradiated withinfrared radiation including a wavelength of 6.7 µm (infrared radiationhaving a peak at a wavelength of 6.7 µm) (radiation source temperature:400° C.) to evaporate the solvent and precipitate crystals. Thetemperature of the solution was 40° C. A heating plate was not used.Infrared radiation was emitted from the infrared heater 10 of the MIMtype. In the infrared heater 10, the first conductor layer 31 (a layerhaving circular metal electrodes 32) made of Au had a height h of 50 nm.The dielectric layer 34 made of Al₂O₃ had a thickness d of 190 nm. Thesecond conductor layer 35 made of Au had a height f of 100 nm. Thecircular metal electrodes 32 had a diameter (corresponding to W1 and W2)of 2.16 µm. The intervals between the metal electrodes (corresponding toD1 and D2) were 1.84 µm. The period (corresponding to Λ1 and Λ2) was 4.0µm. Infrared radiation having a peak at a wavelength of 6.7 µm(half-width: 0.5 µm) was emitted. The crystal form of the precipitatedcrystals was identified as F2 by XRD analysis. The XRD analysis wasperformed with an X-ray diffractometer (product name: Ultima IV,Rigaku).

Example 2

Crystals were precipitated in the same manner as in Example 1 exceptthat the concentration of febuxostat in the test sample was changed from25 mg/mL to 50 mg/mL. The crystal form of the precipitated crystals wasidentified as F1 by XRD analysis.

Example 3

Loxoprofen is known to have a plurality of crystal forms F1 and F2. FIG.4 is a graph of an infrared absorption spectrum of each crystal form.Table 1 shows the absorptivity of each crystal form at wavelengths of3.7 and 6.7 µm in the infrared absorption spectra.

A test sample was prepared by weighing 5 mg of loxoprofen (product codeL0244, Tokyo Chemical Industry Co., Ltd.) into a flat laboratory dish(ϕ32 mm × 16 mm), adding 1 mL of isopropanol (IPA), heating theloxoprofen on a hot plate at 80° C. for 1 minute, and dissolving theloxoprofen with slight stirring (the concentration of loxoprofen in thetest sample was 5 mg/mL). The temperature of the solution was adjustedto 80° C. while the test sample was irradiated with infrared radiationincluding a wavelength of 6.7 µm, and this state was maintained toevaporate the solvent and precipitate crystals. The temperature of thesolution was adjusted by placing the test sample on a heating plate witha Peltier element and using the temperature control function of theheating plate. The crystal form of the precipitated crystals wasidentified as F1 by XRD analysis.

Example 4

Crystals were precipitated in the same manner as in Example 3 exceptthat the concentration of loxoprofen in the test sample was changed from5 mg/mL to 100 mg/mL. The crystal form of the precipitated crystals wasidentified as F2 by XRD analysis.

Example 5

Carbamazepine is known to have a plurality of crystal forms F1, F2, F3,and F4. FIG. 5 is a graph of an infrared absorption spectrum of eachcrystal form. Table 1 shows the absorptivity of each crystal form atwavelengths of 3.0 and 6.7 µm in the infrared absorption spectra.

A test sample was prepared by weighing 25 mg of carbamazepine (productcode C1095, Tokyo Chemical Industry Co., Ltd.) into a flat laboratorydish (ϕ32 mm × 16 mm), adding 1 mL of isopropanol (IPA), heating thecarbamazepine on a hot plate at 80° C. for 1 minute, and dissolving thecarbamazepine with slight stirring (the concentration of carbamazepinein the test sample was 25 mg/mL). The temperature of the solution wasadjusted to 55° C. while the test sample was irradiated with infraredradiation including a wavelength of 3.0 µm, and this state wasmaintained to evaporate the solvent and precipitate crystals. A heatingplate was not used. The crystal form of the precipitated crystals wasidentified as F2 by XRD analysis.

In Example 5, the first conductor layer 31 of the infrared heater 10 hada height h of 49 nm. The dielectric layer 34 had a thickness d of 44 nm.The second conductor layer 35 had a height f of 200 nm. The circularmetal electrodes 32 had a diameter (corresponding to W1 and W2) of 0.54µm. The intervals between the metal electrodes (corresponding to D1 andD2) were 0.46 µm. The period (corresponding to Λ1 and Λ2) was 1.0 µm.Infrared radiation having a peak at a wavelength of 3.0 µm (half-width:0.5 µm) was emitted.

Example 6

Crystals were precipitated in the same manner as in Example 5 exceptthat the concentration of carbamazepine in the test sample was changedfrom 25 mg/mL to 120 mg/mL. The crystal form of the precipitatedcrystals was identified as F3 by XRD analysis.

The results of Examples 1 to 6 are summarized in Table 2.

TABLE 2 Examples Compound Wavelength (µ m) Solvent Concentration (mg/mL)Solution temperature (°C) Crystal form 1 Febuxostat 6.7 IPA 25 40 F2 250 F1 3 Loxoprofen 6.7 IPA 5 80 F1 4 100 F2 5 Carbamazepine 3.01-propanol 25 55 F2 6 120 F3

Examples 1 to 6 show that the solvent, the wavelength, and theconcentration of the compound in the solution could be appropriatelycombined to precipitate a compound with a different crystal form. Fromanother perspective, even with the same solvent and wavelength, thecompound concentration could be changed to precipitate a compound with adifferent crystal form.

Examples 1 and 2 show that, to precipitate febuxostat of the crystalform F1, as described in Example 1, IPA may be used as a solvent, asample may be prepared at a compound concentration of 25 mg/mL, andinfrared radiation with a peak wavelength of 6.7 µm may be emitted. Toprecipitate febuxostat of the crystal form F2, as described in Example2, IPA may be used as a solvent, a sample may be prepared at a compoundconcentration of 50 mg/mL, and infrared radiation with a peak wavelengthof 6.7 µm may be emitted.

Examples 3 and 4 show that, to precipitate loxoprofen of the crystalform F1, as described in Example 3, IPA may be used as a solvent, asample may be prepared at a compound concentration of 5 mg/mL, andinfrared radiation with a peak wavelength of 6.7 µm may be emitted. Toprecipitate loxoprofen of the crystal form F2, as described in Example4, IPA may be used as a solvent, a sample may be prepared at a compoundconcentration of 100 mg/mL, and infrared radiation with a peakwavelength of 6.7 µm may be emitted.

Examples 5 and 6 show that, to precipitate carbamazepine of the crystalform F2, as described in Example 5, IPA may be used as a solvent, asample may be prepared at a compound concentration of 25 mg/mL, andinfrared radiation with a peak wavelength of 3.0 µm may be emitted. Toprecipitate carbamazepine of the crystal form F3, as described inExample 6, IPA may be used as a solvent, a sample may be prepared at acompound concentration of 120 mg/mL, and infrared radiation with a peakwavelength of 3.0 µm may be emitted.

The present application claims priority to International Application No.PCT/JP2020/027266 filed on Jul. 13, 2020, the entire contents of whichare incorporated herein by reference.

What is claimed is:
 1. A refining method for crystallizing a compoundwith at least one crystal form, comprising: setting, as a targetwavelength and a target concentration, a specific infrared wavelengthand a specific concentration at which a specific crystal formprecipitates from a solution of the compound dissolved in a solvent, andusing an infrared radiation apparatus capable of emitting infraredradiation including the target wavelength to evaporate the solvent andprecipitate the specific crystal form while irradiating a solution ofthe compound dissolved in the solvent at the target concentration withinfrared radiation including the target wavelength.
 2. The refiningmethod according to claim 1, wherein the compound has a plurality ofcrystal forms.
 3. The refining method according to claim 1, wherein theinfrared radiation apparatus includes a sheet radiator and a planarheater serving as a heat source.
 4. The refining method according toclaim 1, wherein the infrared radiation apparatus can emit infraredradiation having a peak at the target wavelength.
 5. The refining methodaccording to claim 4, wherein the infrared radiation apparatus emitsinfrared radiation having a peak at the target wavelength from astructure composed of a metal pattern, a dielectric layer, and a metalsubstrate stacked in this order from the outside to the inside, themetal pattern includes metal electrodes of the same shape and sizearranged at regular intervals on the dielectric layer, and a peakwavelength of the infrared radiation changes depending on a width of themetal electrodes.
 6. The refining method according to claim 1, whereinthe compound is febuxostat, loxoprofen, or carbamazepine.